Impaired myocardial relaxation (diastolic dysfunction) is an important component of the pathophysiology of heart disease. This Program Project will study the modulation and regulation of myocardial diastolic function in selected pathologic states. "Modulation" (the alteration of diastolic myocardial properties as assessed in the intact ventricle) will be studied during hypoxia, ischemia, reoxygenation, and reperfusion in intact normal and hypertrophied hearts. "Regulation" (the subcellular events which determine the rate and extent of myocardial relaxation) will be studied in intact hearts by nuclear magnetic resonance (NMR) spectroscopy and in isolated myocytes and myocardial samples by means of patch clamping (to measure sarcolemmal electrical events), and aequorin light emission (to assess intracellular calcium transients and levels). Six projects, a Metabolism Core, and a Morphology Core will provide a spectrum of experimental approaches. Project I will use multivessel coronary stenoses in the pig to study regional diastolic dysfunction during demand ischemia. Project II will use isolated blood perfused rabbit hearts to study diastolic dysfunction during simulated clinical syndromes of "demand" and "supply" ischemia. Project III will study diastolic dysfunction during demand ischemia in hypertrophied isolated blood perfused rabbit hearts to simulate clinical states where coronary stenoses and hypertrophy are both present. Project IV will use isolated perfused rat hearts with three types of hypertrophy: pathologic pressure or volume overload hypertrophy, and physiologic hypertrophy due to exercise conditioning. In Projects IIIV NMR spectroscopy will measure critical intracellular metabolites and cations during hypoxia and ischemia, to identify basic mechanisms of abnormal relaxation, differences relating to the type of hypertrophy, and to provide simultaneous metabolic and mechanical data when interventions are used to modulate diastolic dysfunction. Project V will study diastolic relaxation in isolated cardiac myocytes from animals and man. Project VI will study relaxation in isolated working myocardium from patients with severe hypertrophy and/or heart failure. The research program will provide new information important to the basic understanding of myocardial relaxation and for the clinical care of patients with diastolic dysfunction.